Role of Mitochondia in the Oxidative Stress of Alzheimer's Disease
George Perry, Ph.D.; Dean of the College of Sciences; The University of Texas at San Antonio
September 1 in the Fralin Auditorium, Fralin Hall 102
Hosted by Dr. Bin Xu
George Perry is dean of the College of Sciences, professor of biology, and holds the Semmes Foundation Distinguished University Chair in Neurobiology at The University of Texas at San Antonio. https://www.utsa.edu/sciences/about/dean-bio.html He is recognized in the field of Alzheimer disease research, where he has studied essentially every aspect of the disease, including amyloidosis, oxidative stress, cytoskeleton, metal homeostasis, cell cycle reentry, and mitochondria. For almost 20 years, Perry has been a strong advocate for greater diversity in ideas to move the field forward.
Perry obtained his Bachelor of Arts degree in zoology with high honors from University of California, Santa Barbara. After graduation, he headed to Scripps Institution of Oceanography, Hopkins Marine Station and Woods Hole, and obtained his Ph.D. in marine biology. He then received a postdoctoral fellowship in the Department of Cell Biology at Baylor College of Medicine.
In 1982 Perry joined the faculty of Case Western Reserve University, rising to Professor and Interim Chair of Pathology, and currently holds an adjunct appointment. He is distinguished as the top Alzheimer’s disease researcher by Expertscape with over 1,000 publications, one of the top 100 most-cited scientists in neuroscience and behavior, and one of the top 25 scientists in free radical research. https://en.wikipedia.org/wiki/George_Perry_(neuroscientist)
Perry has been cited over 73,000 (H=135) times and is recognized as a Thompson-Reuters highly cited researcher. He is editor for numerous journals and is editor-in-chief for the Journal of Alzheimer's Disease, the most cited and prolific journal in Alzheimer research. He is a fellow of the American Association for the Advancement of Science, Texas Academy of Science, the Microscopy Society of America, past-president of the American Association of Neuropathologists and the Southwestern and Rocky Mountain Division of the American Association for the Advancement of Science, a member of the Dana Alliance for Brain Initiatives, and a Fulbright Senior Specialist.
Perry is recognized internationally for his research in Alzheimer and promotion of science throughout the Iberian world. He is a Foreign Correspondent Member of the Spanish Royal Academy of Sciences, the Academy of Science Lisbon, and a Foreign Member of the Mexican National Academy of Sciences. He is also a recipient of the National Plaque of Honor from the Republic of Panama Ministry of Science and Technology, and an honorary doctorate from Arturo Prat University, Chile.
Mitochondria may underlie oxidative stress in Alzheimer disease (AD) changes since dysfunction is a prominent and early feature of AD. Recent studies demonstrate that mitochondria are dynamic organelles that undergo continual fission and fusion events which regulate their morphology and distribution. Morphometry showed a small but significant reduction in mitochondria number and enlarged size in AD. Levels of the fission/fusion proteins DLP1, OPA1, Mfn1 and Mfn2C were significantly decreased in AD, yet levels of Fis1 were significantly increased. Interestingly, although all these proteins demonstrate even distribution in the cytoplasm and processes of pyramidal neurons in age-matched control hippocampus, they appeared to accumulate in the soma but not in the processes of pyramidal neurons in AD hippocampus. Given that OPA1, Fis1, and Mfn1/2 are all mitochondrial membrane proteins, the changes in their distribution to soma in AD neurons, suggest changes in mitochondria distribution in these neurons. The expression of fission/fusion proteins was manipulated in M17 cells and primary hippocampal neurons in a way that mimicked their expression changes in AD. These manipulations all reduced mitochondrial density in the cell periphery (M17 cells) or neuronal processes (primary neurons) which correlated with reduced spine numbers (primary neurons).
AβPP and Aβ caused reduced expression of DLP1 and OPA1 while increasing expression of Fis1, consistent with our findings in AD brains. Through time lapse study, we were able to demonstrate that mitochondria were able to fuse with each other but at a much slower rate in AβPP overexpressing cells.
Overall, we concluded that AβPP, through amyloid-b production impairs mitochondrial fission/fusion balance through regulation of expression of mitochondria fission and fusion proteins.
GRANT SUPPORT: This project was supported by a National Institutes of Health grant from the National Institute on Minority Health and Health Disparities (G12MD007591) and by the Semmes Foundation.